Measurement of the function of the retina, either directly or indirectly, is a central component in diagnosing, assessing and monitoring the progression of dysfunction due to disease or trauma. Indirect measurements of the function of the retina include psychophysical tests, e.g. the Humphrey Visual Field test. Direct measurements include electrophysiological measurements such as the electroretinogram (ERG).
Dysfunction of the retina due to disease or trauma is often localized. Further, early detection is of critical importance in cases of potentially blinding eye diseases, as treatments are directed to slowing or halting progression of vision loss. Therefore, measurement of the function of the retina at defined spatial locations on the retina is of great interest.
The Humphrey Visual Field test results in a map of perceptual quality arising from different areas of the retina. However, this psychophysical test has several drawbacks including difficulty in administering the test to young patients or patients with very low vision, and the fact that it measures quality of visual perceptions, and does not directly reflect function at the retina. Further, such psychophysical tests cannot be administered to animals.
The non-invasive measurement of body surface potentials for the purpose of analyzing the bioelectric activity of nerve and muscle tissue has been a known technique in research and clinical environments for many decades. The most common recording strategy for body surface potentials is to use a differential amplifier (FIG. 1). To use a differential amplifier, three electrodes are employed, referred to as the active or recording electrode, the reference electrode, and the ground electrode.
In practice, the recording electrode is placed on the body surface at a position overlying the internal bioelectric tissue of interest, e.g. the heart or the sciatic nerve, with the understanding that the surface potentials reflecting the bioelectric activity of the tissue of interest will be strongest at that location. The potentials recorded at this location will therefore be comprised of the desired signal (potentials related to bioelectric activity of the tissue of interest) plus undesired noise (due to other bioelectric tissues in the body, motion artifacts, or exogenous sources such as nearby power lines).
The reference electrode is placed on the body surface at a location near to, but some distance away from, the active electrode, with the understanding that the body surface potentials recorded at this location will consist of primarily noise similar to the noise recorded by the active electrode, and with the further understanding that the contribution of the bioelectric activity of the tissue of interest to the these recorded potentials will be negligibly small. Therefore, this electrode will record noise only.
The ground electrode is placed on the body surface very distant from the active and reference electrodes, and is used to connect the body to earth ground, which serves as a reference potential, generally taken to be zero Volts.
Referring to FIG. 1, amplifier 10 includes a recording electrode input 14, a reference electrode input 16, a ground electrode input 18, and an output 20. The potentials recorded by the electrodes connected to inputs 14, 16, and 18 are Ea, Er, and Eg, respectively. Eout is the potential at the output 20 of differential amplifier 10, and G is the gain of differential amplifier 10. Differential amplifier 10 performs the following algebraic operation on these potentials: Eout=[(Ea−Eg)−(Er−Eg)]×G.
Because the ground electrode is connected to earth ground and taken to be zero volts, this operation can be simplified as: Eout=[(Ea)−(Er)]×G; or, equivalently: Eout=[(signal+noise)−(noise)]×G, which reduces to: Eout=[signal]×G.
Thus, the output of differential amplifier 10 is the difference in potential between the active and reference electrodes, multiplied by the amplifier gain. The tremendous advantage of the differential amplifier over single-electrode recording is the subtraction of noise from the signal recorded by the active electrode before the gain is applied. Eout is therefore a single potential (or time series of potentials) that is directly related to the underlying bioelectric activity of the target tissue.
Differential amplifier recording is used universally to record the corneal electroretinogram, or ERG. The ERG is a recording of the surface potential at the cornea (transparent portion of the anterior eye), which reflects the underlying bioelectric activity of the neural retina. The ERG is recorded with a number of specific electrode designs.
Some ERG electrodes are monopolar, meaning that only the active electrode contacts the eye surface. However, even monopolar electrodes are used in conjunction with differential amplifiers due to the advantage afforded by these amplifiers of subtracting noise from the signal recorded by the active electrode. Therefore, when using monopolar ERG electrodes, the reference electrode is a skin surface electrode placed on the face near the eye. One example of a monopolar contact lens ERG electrode includes a plastic lens substrate, a single gold foil active electrode, and a single wire, which connects the active electrode to a differential amplifier such as that shown in FIG. 1.
The most common type of ERG electrode is a bipolar design, in which both the active and reference electrodes contact the eye. The most common example of a bipolar ERG electrode is the Burian-Allen contact lens electrode, which includes an active ring-shaped electrode integral to a clear plastic contact lens. An opaque speculum is used to hold the eye lids open and also supports the reference electrode on its lower surface. A twisted pair of wires connects the active and reference electrodes to a differential amplifier. A second type of bipolar ERG contact lens electrode is the Doran GoldLens. This contact lens electrode includes two gold foil ring-shaped electrodes on the inner surface of a contact lens substrate. The electrodes directly contact the corneal surface. Each ring of gold foil is connected to a wire, which in turn connects to a differential amplifier. The ground electrode is typically a skin surface electrode placed on the face or earlobe.
A third example of a bipolar ERG contact lens electrode is described by Grounauer (U.S. Pat. No. 4,386,831), as shown in FIG. 2, which illustrates the connections of the active and reference electrodes to the positive (+) input 14 and negative (−) input 16 of the differential amplifier 10. The design described by Grounauer is a contact lens with four plastic pins 46 protruding from the front surface (see Column 2, lines 10-13; and FIG. 3 of Grounauer). The primary purpose of pins 46 is to hold the eyelids open during an ERG recording session. One of the pins has an axial bore-hole 44, which accepts a metal wire or rod to serve as the active electrode 42 (see Column 2, lines 14-15; lines 18-20; and FIG. 2 of Grounauer). A second pin is used to wrap a wire 40 around, which will then contact the lower eyelid and serve as the reference electrode (see Column 2, lines 46-59 of Grounauer). These two wires (40, 42) would then be connected to a differential amplifier 10 in the typical manner, as described above, resulting in one conventional ERG signal at the amplifier output 20.
A fourth example of bipolar electrodes used for ERG recording is described by Porciatti (US 2003/0149350 A1), as shown in FIG. 3, which illustrates that for each eye 48, one active electrode 50 beneath each eye 48 is connected to the positive input 14 of a differential amplifier 10, and one reference electrode 52 above each eye 48 is connected to the negative input 16 of a differential amplifier 10. Both amplifiers 10 are connected to the same ground electrode 54, on the forehead. Porciatti describes the use of two bipolar electrode pairs to measure the ERG from both eyes simultaneously (see FIG. 1 of Porciatti). Both bipolar pairs of electrodes are referenced to a single ground electrode (see FIG. 1 of Porciatti). Thus, five electrodes are used to perform two simultaneous ERG measurements. The method of Porciatti differs from most ERG measurement techniques in that Porciatti places the active and reference electrodes on the skin surface just below, and just above, the eye, respectively. Porciatti recognizes that by placing the active and reference electrodes at this distance from the bioelectric tissue of interest, namely the retina, that the signal amplitude recorded will be reduced (see paragraph 0022 of Porciatti). Each bipolar pair of electrodes, consisting of one active electrode and one reference electrode, would be connected to a differential amplifier, resulting in one conventional ERG signal per eye.
There are many variations of the ERG technique that are distinguished by the type of stimulus used; some of these variations are the pattern ERG (pERG), multi-focal ERG (mfERG), paired-flash ERG, focal ERG, flicker ERG, photopic ERG, and scotopic ERG. All of these variations use one active electrode, one reference electrode, and a differential amplifier. All of these variations result in one conventional ERG signal at the output of the differential amplifier.
The common feature of all ERG recording described above is that a single ERG voltage signal is obtained from the differential amplifier, which represents the summed activity of the entire retina. It has long been known that the potentials on the eye surface resulting from bioelectric activity of the retina are not spatially uniform. Thus, the magnitude, and possibly the kinetics, of the recorded potential can be influence by the position of the active electrode. This is seen as a complication to ERG recording, and is usually mitigated by using an active electrode that contacts the eye surface over an extended area. The ubiquitous Burien-Allen contact lens electrode, as described above, uses gold foil rings concentric with the pupil as the active and reference electrodes. By contacting the eye surface at several points subtended by the ring, the spatial differences in potential on the eye surface are effectively averaged out via electrical shunting by the gold electrode. Thus, spatial differences in eye surface potentials are effectively ignored in all conventional ERG recording.
There is one example of exploiting the spatial differences in ERG potentials on the eye surface, for the purpose of detecting asymmetry in the eye surface potentials, which may then be taken to indicate an asymmetry in retinal activity as might be associated with retinal injury or disease. Cringle (U.S. Pat. No. 4,874,237) describes the use of four pairs of bipolar electrodes (see FIGS. 1 and 5 of Cringle) contained in a ring, such that the electrodes contact the sclera, peripheral to the cornea, but not the cornea itself. Each bipolar electrode pair may consist of one active electrode in contact with the sclera (white part of eye surface peripheral to the transparent cornea) (see FIGS. 1-4 of Cringle) plus one reference electrode attached to the forehead or cheek (see Column 2, lines 66-68 of Cringle). Alternatively, each bipolar pair may consist of one active electrode plus one reference electrode, which are both in contact with the sclera, positioned along a common radial line extending from the pupil center such that one electrode is located near the corneal margin, and one is slightly more peripheral to the corneal margin (see FIGS. 5-8 of Cringle). In either configuration, there are only four active electrodes in contact with the eye surface, and those four electrodes are confined to the sclera and specifically do not contact the cornea (see Column 1, lines 55-66; Column 2, lines 63-66; Column 4, lines 12-16; Column 4, lines 60-67 of Cringle). In this way, each bipolar pair of electrodes is connected to one differential amplifier, resulting in one ERG signal that is specific to one position on the eye surface. Thus, four distinct ERG signals result.
Cringle then describes taking a further differential measurement between the signals derived from opposing active electrodes (see Column 2, lines 5-9; an FIGS. 1, 2, 5, 6 of Cringle). Thus, two difference signals are produced, where the magnitude of each difference signal is related to the asymmetry in potentials recorded along the specified axis. If the potentials are symmetrical along a given axis, the difference signal along that axis will be zero (see Column 3, lines 13-18 of Cringle). Any non-zero difference indicates an asymmetry in retinal activity along that axis (see Column 3, lines 19-25 of Cringle). However, for any non-zero difference in eye surface potential along one axis, there are an infinite number of possible distributions of underlying retinal activity that could result in that difference. Therefore, the size and location of a retinal lesion cannot be determined using the method proposed by Cringle.
Further, for a retinal lesion located at the center of the retina, as is typical in age-related macular degeneration, the most common cause of blindness in the U.S., the potentials recorded by Cringle's opposing pairs of electrodes would be similar, and thus the presence of the lesion would not be reflected in the output of the amplifiers. The method described by Cringle therefore cannot be used to obtain a map of retinal activity, which would indicate the location and magnitude of any arbitrary retinal lesion. In summary, the method described by Cringle uses four active electrodes on the sclera to detect only asymmetry in retinal activity.
While Cringle indicates that the disclosed approach will provide information about the size and location of a retinal lesion (see Column 4, lines 37-40; Column 4, lines 67-68 of Cringle), no method that would actually provide information about the size and location of a retinal lesion is proposed or suggested. Theoretically, it is not even possible to obtain such location and size information from the output of the system described by Cringle, because the underlying computational problem is under-constrained. In such a system, the computational problem is referred to as the “inverse problem”, in which the locations and magnitude of the underlying bioelectrical sources are solved for using the potentials measured at the eye surface. There simply is not enough information to make such calculations from the type of data obtained by the method and apparatus of Cringle, as explained below.
The distribution of retinal activity can be represented as a distribution of bioelectric dipoles. Each dipole is a vector, which has a position in three dimensional space (e.g., spatial coordinates x, y, z), a direction in three dimensional space (e.g., vector components Dx, Dy, Dz), and a magnitude (M). Since there are seven values required to mathematically describe each dipole (i.e., seven unknowns), it follows that at least seven measurements must be made to solve for the position, direction, and magnitude of each dipole. For the size and location of a retinal lesion to be determined with some degree of specificity, the retina must be divided into a number of equivalent dipoles regions, where each dipole represents the summed activity over a small area of retina. If a human retina is divided into 5 spatial units, each would be approximately 200 square millimeters (mm2) in area and could locate the quadrant of the lesion or its presence at the central region of the retina. To represent each unit by one equivalent dipole, there would be a total of five dipoles, and 5×7=35 unknown quantities to solve for. Similarly, dividing the retina into 100 spatial units, each would be approximately 10 mm2 in area. To represent each of the 100 units by one equivalent dipole, 700 unknown quantities must be determined at the eye surface. If fewer measurements are made, the computational problem will be under-constrained, and a solution cannot be obtained, since the number of measured quantities must always be at least equal to the number of unknown quantities in order to achieve a unique solution to the inverse problem. The methodology described by Cringle measures only 16 quantities (the x, y, z position for each of four active electrode, and the magnitude, M, for the potential at each electrode location). This number of measurements is sufficient only to solve for two equivalent dipoles, which represent the two axes of the retina subtended by the active electrode pairs. These two equivalent dipoles can only reveal asymmetry in the overall retinal activity along these axes, and nothing more. It is impossible to determine the size and location of a retinal lesion from the information provided by Cringle's four scleral measurement locations. Nowhere in the Cringle patent is this problem acknowledged, and nowhere in the Cringle patent is any solution to the inverse problem mentioned. The simple difference measurements described by Cringle only determine the amount of asymmetry in the distribution of retinal activity, and cannot be used to determine the size and location of a retinal lesion.
Many protocols have been developed to directly measure activity of the retina at defined spatial locations using the ERG. These include the focal ERG and multi-focal ERG methods. These methods also have significant drawbacks. The focal ERG measures function only in the central retina, and many conditions of great clinical interest (potentially blinding conditions of high prevalence, e.g. retinitis pigmentosa or diabetic retinopathy) first present in the peripheral retina. The multi-focal ERG (mfERG) measures approximately the central 50 degrees of visual field. The mfERG takes several minutes to record, during which the subject must fixate on a small target, making it difficult to record from very young patients or patients with low central vision. Further, the mfERG signal is not a true bioelectric signal, and physiological interpretation of the signal remains a challenge.
As noted above, eye diseases often result in localized dysfunction of the retina. In a clinical setting, electroretinography is a useful, non-invasive procedure for determining retinal activity in which electrical potentials at the eye surface are measured upon exposing the retina to a light stimulus. These surface potentials result from activity generated by the retina in response to the stimulus. The electrical potential at a given position on the eye surface is not related to the activity of only one unique retinal position. Rather, the potential at a given position on the eye surface is the sum of contributions from activity of all portions of the retina. In conducting a typical ERG, a single electrode is positioned on the anterior surface of a subject's eye and a second electrode, usually referred to as an “indifferent” or reference electrode is positioned to complete an electrical connection with the patient's upper anatomy. The indifferent electrode may be placed, for example, in the mouth or may be electrically coupled to the subject's ear or other convenient locus for such connection. The retina is then exposed to a light source and, in response, generates one or more electrical signals, which are then studied. An ERG is a record of the resulting electrical signals.
Retinal illumination during an ERG may be conducted in a number of ways. For example, a first set of electroretinographic readings may be taken in normal room light. In a second step, the lights may be dimmed for a significantly long period of time (on the order of 20 minutes), and readings are taken while the subject's retina is exposed to a light source. That is, after prolonged period in a dark environment, electrophysiological readings are taken at the onset of retinal exposure to light, and for a time period shortly thereafter. For example, after a sufficient time for adaptation of the retina to the dark environment has passed, a bright flash may be directed to the subject's retina with electroretinogram readings being taken. Each electroretinogram reading will differ depending upon the light conditions to which the patient's retina is subjected. However, standard responses have been established for each type of test and various useful conclusions can be drawn from excursions from such standardized data. In each test, the retinal response to each illumination is typically in the form of a voltage versus time waveform. Different types of waveforms have been defined for normal retinal responses. It is expected in a healthy subject, for example, that an electroretinogram shows a-wave and b-wave patterns normal in shape and duration, with appropriate increases in electrical activity as the stimulus intensity is increased.
As indicated above, electrodes used to measure corneal potentials may be mounted on a contact lens for convenient application in an outpatient setting. Such an electrode typically measures summed activity from the entire retina. In general, the electrical changes caused by the different major cell types of the retina (e.g., rod and cone photoreceptors, bipolar cells, horizontal cells, amacrine cells, ganglion cells, and Muller cells) tend to overlap in time, thus complex and varying waveforms are observed. The most prominent wave is the b-wave and the height of this wave can provide an indication of the subject's sensitivity to the illumination source. Tests can be conducted with illumination sources of different spectral content, intensity, kinetics, spatial patterns and spatial contrast, etc., and the results can be studied to determine the state of the subject's ocular health.
Simplified electrical models of the eye have been described in the literature. The first analytical account of the electric fields generated by retinal activity was given by Krakau, Acta Opthalmologica; 1959; 36(11):183-207, who used analytical methods based on Helmholz's theory of electromotive surface to estimate the potentials at the corneal surface. The eye was modeling as a perfect sphere containing no intraocular structures. Krakau's model assumed radial symmetry, and thus the eye model was reduced to two dimensions.
Doslak, Plonsey and colleagues extended the work of Krakau by incorporating three major ocular structures, the sclera, cornea, and lens. The region defined in this model as the “sclera” actually represented the combined retina, retinal pigment epithelium, choroid and sclera. This group maintained the assumption of axial symmetry, and therefore reduced the model to two dimensions (see Doslak et al., IEEE Trans. Biomed. Eng.; 1980; 27(2):88-94; Doslak et al., Med. & Biol. Eng. & Comp., 1981; 19:149-156). This work necessarily used a finite difference algorithm to solve Laplace's equation for the model. This model did include the R-membrane, which arises in the retinal pigment epithelium.
Job. et al., Med. & Biol. Eng. & Comp., 1999; 37:710-719, extended the model of Doslak to three dimensions, including the same level of anatomical detail (sclera, cornea, and lens), and used a similar finite difference approach. Similar to the Doslak model, the neural retina or sublamina of the neural retina were not distinctly defined in terms of anatomy or electrical properties. The model region considered to represent the “sclera” actually represented the combined retina, retinal pigment epithelium, choroid and sclera.
Davey et al., IEEE Trans. Biomed. Eng.; 1988; 35(11):942-7, modeled the eye as a two-dimensional oval of uniform conductivity. This model had only three regions defined by distinct electrical properties: the eye, the medium in front of the eye and the medium behind the eye. No intraocular structures were included in the model. The simplified geometry was required in order to implement the analytical methods used.